Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical .beta.-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins were earlier regarded as potent ocular hypertensives; however, evidence accumulated in the last decade shows that some protaglandins are highly effective ocular hypotensive agents and are ideally suited for the longterm medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505). Such prostaglandins include PGF.sub.2.alpha., PGF.sub.1.alpha., PGE.sub.2, and certain lipid-soluble esters, such as C.sub.1 to C.sub.5 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
In the U.S. Pat. No. 4,599,353 certain prostaglandins and their derivatives, in particular PGE.sub.2 and PGF.sub.2.alpha. and the C.sub.1 to C.sub.5 alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management. It was suggested that the C.sub.1 to C.sub.5 alkyl esters of PGF.sub.2.alpha., such as its methyl and isopropyl esters, would be particularly advantageous due to their lipid-solubility which would permit more ready penetration through the cornea and would lower the effective amounts of these compounds.
Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al., Invest. Ophthalmol. Vis. Sci. 28(suppl), 284 (1987)].
The isopropyl ester of PGF.sub.2.alpha. has been shown to have significantly greater hypotensive potency than the parent compound, which was attributed to its more effective penetration through the cornea. In 1987 this compound was described as "the most potent ocular hypotensive agent ever reported" [see, for example, Bito, L. Z., Arch. Ophthalmol. 105, 1036 (1987), and Siebold et al., Prodrug 5, 3 (1989)]. However, the use of PGF.sub.2.alpha. 1-isopropyl ester or other C-1 alkyl esters in the clinical practice, is considerably limited by formulation difficulties due to their hydrophobic nature. Their ophthalmic formulations can only be made with oily carriers, such as sterile anhydrous peanut oil.
Also, whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF.sub.2.alpha. and its prodrugs, e.g. its 1-isopropyl ester, in humans. The clinical potential of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma, is greatly limited by these side effects.
In a series of co-pending United States patent applications assigned to Allergan, Inc. prostaglandin esters with increased ocular hypotensive activity accompanied with no or substantially reduced side-effects are disclosed. The co-pending U.S. Ser. No. 386,835 (filed Jul. 27, 1989), relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF.sub.2.alpha.. Intraocular pressure reducing 15-acyl prostaglandins are disclosed in the co-pending application U.S. Ser. No. 357,394 (filed May 25, 1989). Similarly, 11,15- 9,15- and 9,11 -diesters of prostaglandins, for example 11,15-dipivaloyl PGF.sub.2.alpha. are known to have ocular hypotensive activity. See the co-pending patent applications U.S. Ser. Nos. 385,645, 386,312 and 386,834 (all filed Jul. 27, 1989). PGF 1-alcohols and their use as ocular hypotensives are disclosed in co-pending patent application U.S. Ser. No. 07/538,204 (filed Jun. 14, 1990). Other prostaglandin derivatives for ocular use are, for example, disclosed in U.S. Ser. No. 07/611,029 (filed Nov. 9, 1990 ), U.S. Ser. No. 07/624,659 (filed Dec. 10, 1990) and U.S. Ser. No. 07/623,234 (filed Dec. 6, 1990). The disclosures of these patent applications are hereby expressly incorporated by reference.